Pain has two components, each involving activation of sensory neurons. The first component is the early or immediate phase when a sensory neuron is stimulated, for instance as the result of heat or pressure on the skin. The second component is the consequence of an increased sensitivity of the sensory mechanisms innervating tissue which has been previously damaged. This second component is referred to as hyperlagesia, and is involved in all forms of chronic pain arising from tissue damage, but not in the early or immediate phase of pain perception.
Thus, hyperalgesia is a condition of heightened pain perception caused by tissue damage. This condition is a natural response of the nervous system apparently designed to encourage protection of the damaged tissue by an injured individual, to give time for tissue repair to occur. There are two known underlying causes of this condition, an increase in sensory neuron activity, and a change in neuronal processing of nociceptive information which occurs in the spinal cord. Hyperalgesia can be debilitating in conditions of chronic inflammation (e.g. rheumatoid arthritis), and when sensory nerve damage has occurred (i.e. neuropathic pain).
Two major classes of analgesics are known: (i) non steroidal anti-inflammatory drugs NSAIDs) and the related COX-2 inhibitors; and (ii) opiates based on morphine. Analgesics of both classes are effective in controlling normal immediate, or nociceptive pain. However, they are less effective against some types of hyperalgesic pain, such as neuropathic pain. Many medical practitioners are reluctant to prescribe opiates at the high doses required to affect neuropathic pain because of the side effects caused by administration of these compounds, and the possibility that patients may become addicted to them. NSAIDs are much less potent than opiates, so even higher doses of these compounds are required. However, this is undesirable because these compounds cause irritation of the gastrointestinal tract.
Adenosine A1 receptor agonists are known to act as powerful analgesics (Sawynok, Eur J Pharmacol. (1998) 347, 1-11), and adenosine A2A receptor agonists are known to act as anti-inflammatory agents. However, development of adenosine-based therapies has generally been precluded because they have unacceptable side effects. Selective A1 receptor agonists cause bradycardia, and A2A receptor agonists cause widespread vasodilation with consequent hypotension and tachycardia.
Spongosine is a compound that was first isolated from the tropical marine sponge, Cryptotethia crypta in 1945 (Bergmann and Feeney, J. Org. Chem. (1951) 16, 981, Ibid (1956) 21, 226). Spongosine was the first methoxypurine found in nature, and is also known as 2-methoxyadenosine, or 9H-purin-6-amine, 9-α-D-arabinofuraosyl-2-methoxy.
The first biological activities of spongosine were described by Bartlett et al. (J. Med. Chem. (1981) 24, 947-954) who showed that this compound has muscle relaxant, hypothermic, hypotensive, and anti-inflammatory activity in rats (anti-inflammatory activity was assessed by inhibition of carrageenan-induced oedema in a rat paw).
The affinity of spongosine for the rat adenosine A1 and A2A receptors has been determined. The Kd values obtained were 340 nM for the A1 receptor and 1.4 μM for the A2A receptor (Daly et al., Pharmacol. (1993) 46, 91-100). In the guinea pig, the efficacy of spongosine was tested in the isolated heart preparation and the EC50 values obtained were 10 μM and 0.7 μM for the adenosine A1 and A2A receptors, respectively (Ueeda et al J Med Chem (1991) 34, 1334-1339). In the early 1990s the other adenosine receptors (the A2B and A3 receptors) were cloned, but the activity of spongosine at these receptors was never investigated. The low potency and poor receptor selectivity of this compound led to it being largely ignored as more and more potent and receptor selective novel compounds were synthesised.